Lincomycin type compounds and process for making them

ABSTRACT

A 1&#39;&#39;-DEMETHYLLINCOMYCIN-TYPE COMPOUND IS REACTED WITH AN ALDEHYDE TO FORM AN ANTIBACTERIALLY ACTIVE ALKYL 6 - DEAMINO - 6-(TETRAHYDRO-1-OXO-PYRROLO-IMIDAZOLYL)-ATHIOLINCOSAMINIDE OF THE FORMULA   1-(O=),2-((3,4,5-TRI(HO-),6-(R-S-)TETRAHYDROPYRAN-2-YL)-   C(-CH3)(-CH(-X)-CH3)-),3-R2,6-R1-PERHYDROPYRROLO(1,2-C)-   IMIDAZOLE   WHERE R, R1 AND X ARE RADICALS OF THE 1&#39;&#39;-DEMETHYLLINCOMYCIN-TYPE COMPOUND AND R2 IS THE RADICAL OF THE ALDEHYDE.

United States Patent 01 lice 3,758,454 Patented Sept. 11, 1973 ABSTRACTOF THE DISCLOSURE A 1'-demethyllincomycin-type compound is reacted withan aldehyde to form an antibacterially active alkyl 6 deamino6-(tetrahydro-1-oxo-pyrrolo-imidazolyl)-athiolincosaminide of theformula where R, R and X are radicals of the 1-demethyllincomycin-typecompound and R is the radical of the aldehyde.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to a novelprocess for making derivatives of N-demethyllincomycin-type compoundsand to certain novel compounds produced by this process. Moreparticularly it involves a process for making alkyl 6 deamino 6(tetrahydro-l-oxo-pyrrolo-imidazolyl)- a-thiolincosaminides of theformula wherein X is chlorine, bromine, iodine, hydroxy, loweralkoxy,hydroxyloweralkoxy, sulfhydryl, lower-alkylthio, hydroxyloweral kylthio;or an aromatic benzenoid hydrocarbonthio radical substituted by zerothrough 3 hydroxy, halo, nitro, dialkylamino groups containing in allnot more than 12 carbon atoms; R is alkyl of one to 4 carbon atoms,inclusive; or a radical of the formula CH CH --OR wherein R is hydrogenor alkyl of one to 4 carbon atoms, inclusive; R is hydrogen orlower-alkyl; and R is an aliphatic or cycloaliphatic hydrocarbon radicalhaving from zero through three valences satisfied by halogen,

alkoxy, alkenyloxy, alkylthio, alkenylthio, hydroxy, nitro, epoxy,epoxyalkoxy, alkanoyloxy, dialkylamino, carboxy, or carbalkoxy, andcontaining in all not more than 18 carbon atoms; or an aromatichydrocarbon radical of the benzene series having from zero through threevalences satisfied by hydroxy, alkoxy, alkanoyloxy, benzyloxy, phenoxy,tolyoxy, halogen, nitro, mercapto, alkylthio, amino, alkylamino,dialkylamino, or methylene diox'y and containing in all not more than 18carbon atoms; or a hydrocarbon radical containing a heterocycle of thegroup furan, thiophene, pyridine, and indole having zero to threesubstituents of the group hydroxy, alkoxy, alkanoyloxy, benzyloxy,phenoxy, alkoxyphenyl, alkoxybenzyl, mercapto, alkylthio, phenylthio,benzylthio, halogen, nitro, amino, alkylamino, dialkylamino, carboxy,and carbalkoxy and containing in all not more than 18 carbon atoms; inwhich an N-demethyllincomycintype compound of the formula HO 0 0 Nwherein R, R and X are as given above is reacted under non-acidconditions with an aldehyde of the formula R CHO wherein R is as givenabove.

The novel compounds of the invention (Formula I) have antibacterialproperties like lincomycin and can be used like lincomycin to controlsusceptible bacterial.

DETAILED DESCRIPTION OF THE INVENTION wherein R is as above an Ac isacetyl with an alcohol in the presence of acetic acid. The reactionproceeds readily with gentle heating, for example, at the refluxtemperature. The acetyl groups are then removed by hydrazinolysis in amanner already known in the art and the resulting alkyl 7-O-substituted-a-thiolincosaminide is then acylated in the appropriateL-Z-pyrrolidinecarboxylic acid by procedures already known in the art.

When X is loweralkylthio or hydroxyloweralkylthio, the alcohol in theabove reaction is substituted by a sulfide, for example, methyl sulfideor 2-hydroxyeth'yl methyl sulfide. Aromatic sulfides, for example,phenyl sulfide, benzyl sulfide, with zero through three substituents aslisted above also form 7 (S)-Sl1bStltllIed-OL-IhiOIIHCOSZUIlinides.These 7(8)-substituted-u-thiolincosaminides are converted toantibacterially active compounds by N-acyla tion with anL-Z-pyrrolidinecarboxylic acid as above.

The starting aldehydes R CHO are known in the art. The process isbroadly applicable to any aldehyde and antibiotically active compoundsare obtained independently of the specific character of the aldehyde.Some aldehydes give compounds with more lincomycin-like activity, othersgive compounds with less. The reaction, however, appears to be a generalone and proceeds with any aldehyde and therewith give antibacteriallyactive compounds having lincomycin-type activity.

Thus the aldehyde can be any aliphatic, saturated or unsaturated;cycloaliphatic, saturated or unsaturated; aromatic; or heterocyclicaldehyde; provided only that R is a radical that is nonreactive with theN-demethyllincomycin-type starting compound of Formula I.

Novel compounds, having lincomycin-like activity to a greater or lesserdegree, which can be used like lincomycin to control susceptiblebacteria, are obtained when X, R, and R are as given above and R ishydrogen or methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl pentadecyl,hexadecyl, heptadecyl, octadecyl, and the isomeric forms thereof;bromochloromethyl, butoxymethyl, butylthiomethyl, tert.butylthiomethyl,chlorodifiuoromethyl, cyclohexadienylmethyl, cyclohexylmethyl,cyclohexylidenemethyl, cyclopentylmethyl, cyclopentenylmethyl,cyclopentylidenemethyl, dibromomethyl, dichlorornethyl,diethylaminomethyl, dihydroxymethyl, diisopropylarninornethyl,dimethylaminomethyl, ethoxymethyl, fluoromethyl, hydroxymethyl,iodomethyl, methoxymethyl, methylthiomethyl, nitromethyl,propylthiomethyl, tribromomethyl, trichloromethyl, trifluoromethyl, andtriiodomethyl, 2-allyloxyethyl,

2-allyloxy-1,l-dimethylethyl,

1- (allylthio ethyl, 2-amino-1-hydroxyethyl,

2-b romoethyl, 2-bromo-2,2-difluoroethyl,

Z-bromo- 1 l-dimethylethyl, 1-bromo-2-ethoxyethyl,l-bromo-Z-methoxyethyl,

l-bromol-methylethyl, 2-butoxyethyl,

Z-tert-butoxyl-chlorol-methylethyl, 2-(butylarnino)-1, l-dimethylethyl,1-(tert.butylamino)-1-methylethyl, l-chloroethyl,

2-chloroethyl,

2-chloro-1, l-dimethylethyl, 1-chloro-2-ethoxyethyl,1-ch1oro-2-methoxyethyl, 1-chloro-2-methoxy- 1 -methylethyl,l-chlorol-methylethyl, 1,2-dibromoethyl,

Z-dibutylamino- 1 l-dimethylethyl,

1, 1-dimethylethyl,

1,1-dichloroethyl,

1,2-dichloroethyl,

2,2-dichloroethyl,

2,2-dichlorol-methoxyethyl, 2,2-diethoxyethyl,

2,2-diethoXy-1, l-dimethylethyl, 2,2-diethoxyl-methylethyl,Z-(diethylamino ethyl, 2-(diethylarnino)-1,1-dimethylethyl, 1-(diethylamino -1-methylethyl, 2-(diethylamino)-1-methylethyl,

1 ,Z-dihydroxyethyl (from glyceraldehyde 1 ,Z-dimethoxyethyl,

1- (dimethylamino ethyl,

2- (dimethylamino ethyl, 2-(dimethylamino)-1,1-dimethylethyl, 1-(dimethylamino l-Inethylethyl,

4 1, l-di (methylthio) ethyl, 1,2-dinitroethyl, 2,2-dinitroethyl,1,2-epoxyethyl, 2-( 1,2-epoxypropoxy ethyl, 2- 2,3-epoxypropoxy) ethyl,Z-ethoxyethyl, 2-ethoxy-1, l-dimethylethyl, l-ethoxyl-rnethylethyl, 1-ethylthio l-methylethyl, 2- (ethylthio) -1-methy1ethyl, l-fiuoroethyl,l-fiuorol-methylethyl, Z-hydroxyethyl, l-hydroxyl-methylethyl,2-isobutoxy-1, l-dimethylethyl, 2-is obutoxy- 1-m ethyl- 1 -nitroethyl,2-isopropoxy-1, l-dimethylethyl, 2-isobutoxy-1-methyl-l-nitroethyl,2-isopropoxy-1,1-dimethylethyl, 1- (isopropylthio l-methylethyl,l-methoxyethyl, 2-methoxyethyl, Z-methoxy-1,1-dimethylethyl,l-methoxyl-methylethyl, 2-methoxy-1-methylethyl, l-rnethoxyl-nitroethyl,l-methyll-methylthioethyl, 1-methyl-2-methylthioethyl, l-methyll-nitroethyl, l-methyl-Z-nitro ethyl, 1- (methylthio) ethyl, 2- methylthio)ethyl, 2-propoxyethyl, 2- (propylthio) ethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 1,2,2-trinitroethyl, and 2- vinyloxy ethyl; 1-(allyloxy)methyl] 1- (isobutoxymethylpropyl 1 l-bis (hydroxymethylpropyl, 2,3-bis (methylthio) propyl, l-bromopropyl, Z-bromopropyl,1-bromo-2-butoxypropyl, 1-bromo-2,2-dimethylpropyl,l-bromol-ethoxypropyl, 1-bromo-2-ethoxypropyl, 1-bromo-2-methylp ropyl,3-butoxypropyl, 2-butoxy-3 -hydroxypropyl, l-butoxyl-methylpropyl,2-butoxy-2-methylpropyl, 2-(butylth'io)propyl, l-chloropropyl,2-ch1oropropyl, 3 -chloropropyl, l-chloro-Z-ethoxypropyl,1-chloro-3-hydroxypropyl, Z-chloro- 1 -hydroxypropyl, l-chloro- 1,2,Z-trimethylpropyl, 1 ,1-dibromopropyl, 2,3-dibromopropyl,2,3-dichloropropyl, 3,3-dichloropropyl, 1,1-dichloro-2,Z-dimethylpropyl,1,3 -dichloro -2-ethoxyp ropyl, 1,3-dichloro-2-methoxypropyl,l-diethylaminopropyl, 1- (diethylamino)methyl] propyl, 1- (diethylaminomethy1]-2-methylpropyl, 2, 2-diethoxypropyl, 2,3-diethoXy-2-hydroxypropyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl,

1 9 S-bromo-S-indolyl, -chloro-3-indolyl, 1 ,2-dimethyl-3-indolyl, 1-(Z-dimethylaminoethyl -3-indolyl, 1- dimethylaminomethyl) -3-indolyl,2-methoxy-3-indolyl, 5-methoxy-3 -indolyl, Z-methoxy-1-methyl-3-ind0lyl,1-methyl-3-indolyl, 2-methyl-3-indolyl, 5-methyl-3-indolyl,1-methyl-2-phenyl-3 -indolyl, 2, 3-dimethyl-5 -indoly1, 2,3-dimethyl-6-indolyl, 2,3 -dimethyl-7-indolyl, 3 -indolyl-hydroxymethyl, 2-3-indolyl) ethyl, 1-amino-2-( 3 -indolyl) methyl, 2-pyridylmethyl,B-pyridylmethyl, 2-pyn'dylrnethylvinyl, 3-pyridylmethylvinyl, -py y p py3-hydroxy-3- 2-pyridyl )propyl, 3-hydroxy-3 -methyl-3- (2-pyridylpropyl, 3-hydroxy-3-phenyl-3- (2-pyridyl propyl, -p y 3-pyridyl,4-pyridy1, 3-amino-2-pyridyl, 3-butyl-2-pyridyl, 4-chloro-2-pyridyl,4-chloro-5-ethyl-2-pyridyl, 4-chloro-6-methyl-2-pyridyl,4-ethoxy-5-ethyl-Z-pyridyl, 3-ethyl-2-pyridyl, 5-ethyl-4-methoxy-2-pyridyl, 5-ethyl-4-methyl-2-pyridyl, 3-hydroxy-2-pyridyl, 6- (hydroxymethyl -2-pyridyl, 3-methoxy-2-pyridyl,4-methoxy-2-pyridyl, 4-rnethoxy- 6-methyl-2-pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5 -methyl- 2-pyridyl,6-methyl-2-pyridyl, 6-methyl-4-nitro-2-pyridyl, 5-nitro-2-pyridyl, 3-pentyl-2-pyridyl, 3 -propyl-2-pyridyl, 2-amino-3 -pyridyl,6-dimethylamino-3-pyridyl, 5-hydroxy-4- (hydroxymethyl)-6-methyl-3-pyridyl, 4 methyl-3-pyridyl, 5-methyl-3-pyridyl, 2-2-pyridyl ethyl, 2- (p-chlorophenyl )-2- (2-p yridyl) ethyl, 2-phenyl-2-2-pyridyl) ethyl, 2- 3-pyridyl ethyl, and 2- (p-chlorophenyl) -2-3-pyridyl ethyl.

The reaction between the starting compound for Formula II and thealdehyde, R CHO proceeds readily at room temperature or with mildheating, say up to the boiling point of the reaction mixture. Theproportions are not critical through ordinarily a large excess of thealdehyde is desirable for good yields. If the aldehyde is water solubleit may be used as an aqueous solution. The excess aldehyde may alsofunction as a solvent or vehicle for the reaction except where solidaldehydes are employed. Another solvent is then used, for example,tetrahydrofuran, lower alcohols and ethers, dioxane, chlorinatedhydrocarbon solvents, dimethylsulfoxide, acetonitrile, and benzene. Evenso a large excess of the aldehyde 20 is desirable. Ordinarily it will besuflicient to use between a 2 and a 20 fold excess.

The reaction is effected under non-acidic conditions. Here, too, theconditions are not critical as long as the reaction is definitely notacidic. If the starting compound is in the form of the hydrochloridesalt, or other acid addition salt, suflicient base must be used toneutralize the acid. If not it is sufiicient simply to mix the free basestarting compound with the aldehyde and a neutral solvent such as excessaldehyde, Water, tetrahydrofuran, or the like. Additional base can beused if desired and some times better yields are obtained if thereaction is effected in the presence of added base, i.e., base otherthan the free base starting compound. Aromatic amines can be used withadvantage for this purpose. Ordinarily when an aqueous menstruum is usedit will be suflicient to adjust the pH of the reaction mixture tobetween about pH 8 and about pH 10 or 11. Where an anhydrous or asubstantially anhydrous menstruum is used, as for example whentetrahydrofuran is used as the solvent or an excess of anhydrousaldehyde, a water adsorbing polymer, such as a molecular sieve, can beadded to take up the water of formation.

The compounds of the invention (Formula I) can exist in either the freebase form or in the form of an acid addition salt. Unless otherwisespecified or otherwise dictated by the context both the acid additionform and the free base form is intended. These acid addition salts canbe made by neutralizing the free base with the appropriate acid.Suitable acids for this purpose include hydrochloric, sulfuric,phosphoric, thiocyanic, fiuosilicic, hexafluoroarsenic,hexafluorophosphoric, acetic, succinic, citric, lactic, maleic, fumaric,pamoic, cholic, palmitic, mucic, camphoric, glutaric, glycolic,phthalic, tartaric, lauric, stearic, salicylic, 3-phenylsalicylic,5-phenylsalicylic, 3-methylglutaric, orthosulfobenzoic,cyclohexanesulfamic, cyclopentanepropionic, 1,2-cyclohexanedicarboxylic,4-cyclohexenecarboxylic, octadecenylsuccinic, octenylsuccinic,methanesulfonic, benzenesulfonic, helianthic, Reineckes,dimethyldithiocarbamic, hexadecylsulfamic, octadecylsulfamic, sorbic,monochloroacetic, undecylenic,

-hydroxyazobenzene-4-sulfonic, octadecylsulfuric, picric, benzoic,cinnamic, and like acids.

The acid-addition salts can be used for the same purposes as the freebase or they can be employed to upgrade the same. For example, the freebase can be converted to an insoluble salt, such as the picrate, whichcan be subjected to purification procedures, for example, solventextractions and washings, chromatography, fractional liquidliquidextractions, and crystallization and then used to regenerate the freebase form by treatment with alkali or to make a dilferent salt bymetathesis. 01- the free base can be converted to a water-soluble salt,such as the hydrochloride or sulfate and the aqueous solution of thesalt extracted with various water-immiscible solvents beforeregenerating the free base form by treatment of the thus-extracted acidsolution or converted to another salt by metathesis.

The free bases can be used as bulfers or as antacids. They react withisocyanates to form urethanes and can be used to modify polyurethaneresins. The thiocyanic acid addition salt when condensed withformaledhyde forms resinous materials useful as pickling inhibitorsaccording to U.S. Pats. 2,425,320 and 2,606,155. The free bases alsomake good vehicles for toxic acids. For example, the fluosilicic acidaddition salts are useful as mothproofing agents according to U.S. Pats.1,915,334 and 2,075,359 and the hexafluoroarsenic acid andhexafluorophosphoric acid addition salts are useful as parasiticidesaccording to U.S. Pats. 3,122,536 and 3,122,552.

The invention may now be more fully understood by referring to thefollowing examples in which solvent ratios are by volume, the partsotherwise by weight, and the c.g.s. system is used.

21 EXAMPLE 1 Methyl 7-chloro 6,7,8 trideoxy-6-(5,6,7,7aa-tetrahydrol-oxo60c propyl-1H-pyrrolo[1,2-c]imidazol-2-(3H)-yl)-l-thio-L-threo-a-D-galacto-octopyranoside 1 demethylclindamycinhydrochloride, 7(S)-chloro- 7-deoxy-1-demethyllincomycin hydrochloride(2.0 g.) was dissolved in 200 ml. of water. The solution was mixed with20 ml. of 1 N sodium hydroxide and 20 ml. of formaldehyde solution (37%w./v.). The mixture was allowed to stand at ambient temperature for 1.5hrs. The solution was free-dried and then triturated with 50 ml. ofwater. The crystalline material formed, was isolated by filtration anddried. Yield 1.5 g. methyl 7-chloro-6,7,8- trideoxy 6(5,6,7,7aa-tetrahydro-1-oxo-6a-propyl-1H- pyrrolo[1,2-c]imidazol 2( 3H)yl)-1-thio-L-threoa- D- galacto-octopyranoside having the followingcharacteristics: [a] +188 (c., 1.04, water).

Analysis.Calcd. for C H ClN- O S (percent): C, 51.23; H, 7.40; Cl, 8.40;N, 6.64; S, 7.60. Found (percent): C, 50.62; H, 7.26; Cl, 8.14; N, 6.38;S, 7.54.

By substituting 1'-dimethylclindamycin hydrochloride by its 4-epimer,7(S) chloro-7-deoxy-1'-demethyl-4- epilincomycin hydrochloride of theformula l i l r o1-- nert...

lL iCHs OH and (S) chloro 7 deoxy-l'-demethyl-4'-epilincomycinhydrochloride of the formula on.I l ---o1 |-l NH 22 the correspondingepimers, methyl 7-chloro-6,7,8-trideoxy- 6-(5,6,7,7aa-tetrahydro "1 oxo6ocand fl-propyHH- pyrrolo [l,2-c]imidazol2(3H)-yl)-1-thio-D-erythrou-D-galactooctopyranosides are obtained.

By making like substitutions in the following examples the correspondingepimers are obtained.

EXAMPLE 2 Methyl 7-chloro 6,7,8 trideoxy 6-(5,6,7,7aa-tetrahydro 1 oxo6a-pentyl-1H-pyrrolo[1,2-c]imidazol- 2-(3H) yl) 1thio-L-threo-a-D-galacto-octopyranoside Two g. of 1'-demethyl 4depropyl-4'-n-pentylclindamycin hydrochloride was dissolved in 400 ml.of water. The clear solution was mixed with 50 ml. of aqueousformaldehyde solution (37%) and 50 ml. of 1 N aqueous sodium hydroxidesolution. The solution turned cloudy, therefore 150 ml. of dioxane wasadded. The reaction mixture was allowed to stand at room temperature for1.5 hrs. The solution was freeze-dried and then triturated with 50 ml.of water. Insoluble material was isolated by filtration and dried,yielding methyl 7-chloro-6,7,8-trideoxy-6-(S,6,7,7,7aa-tetrahydro 1oxo-6a-pentyl-1H-pyrrolo[l,2-c]imidazol 2(3H)-yl) 1 thio-L-threo-a-D-galacto-octopyranoside having the following characteris tics: [u] +191(c., 1, percent ethanol).

Analysis.--Calcd. for C H ClN SO -H O (percent): C, 51.50; H, 7.51; C],7.60; N, 6.00; S, 6.86. Found (percent): C, 51.16; H, 7.28; Cl, 6,43; N,6.07; S, 6.66.

EXAMPLE 3 Methyl 7-bromo 6,7,8 trideoxy 6-(5,6,7,7aa-tetrahydro 1 oxo-6apropyl-1H-pyrrolo[1,2-c]imidazo1-2(3H)-yl)-1-thio-a-D-galacto-octopyranoside To a solution composed of8.0 g. of 1'-demethyl-7 (S)- bromo-7-deoxylincomy-cin-HCl, ml. 37%formaldehyde solution and 400 ml. of water was added 20 ml. of 1 Nsodium hydroxide. After stirring at 25 for 2 hrs. the reaction wasfreeze-dried. The solid residue was dissolved in 75 ml. of water,adjusted to pH 7.5 with 4 N hydrochloric acid and stirred for 1 hour.The solid precipitate was collected and dried to yield 5.7 g. of methyl7- bromo-6,7,8trideoxy-6-(5,6,7,7aa-tetrahydro-1-oxo-6orpropyl-1H-pyrr0lo[1,2-c]-imidazol-2(3H)-yl1 thio-L- threo-a-D-galacto-octopyranoside having the followingcharacteristics: [0:1 :3 +229 (c., 0.98, CHCl Analysis.-Calcd. for C HBrN O S (percent): C, 46.25; H, 6.69; Br, 17.10; N, 5.99; S, 6.86. Found(percent): C, 45.94; H, 7.41; Br, 16.71 N, 5.93; S, 6.49.

A portion of this material was dissolved in acetone and ethanolic-HCladded to pH 1. The hydrochloride salt which precipitated was collectedand dried.

EXAMPLE 4 Methyl 7-bromo 6,7,8 trideoxy-6-(5,6,7,7aa-tetrahydro 1oxo-6u-propyl 1H pyrrolo[l,2-c]imidazl- 2 3H -yll-thio-L-threo-a-D-galacto-octopyranoside Part A-4 Methyl6,8-dideoxy-6-(5,6,7-7aa-tetrahydro 1 oxo-6apropyl-lHpyrrolo[1,2-c]imidazol 2(3H)-yl)-l-thio-D-erythro-a-D-galacto-octopyranoside T3 iom Part B-4 Methyl 7 bromo6,7,8 trideoxy 6 (5,6,7aa-tetrahydro-l-oxo 60c propyl 1Hpyrrolo[1,2-c]imidazol-2(3H)-yl)-l-thio-L-threo-a-D-galacto-octopyranoside A solution composedof 40 g. of the product of part A4, 157 g. of triphenylphosphine and 2l. of acetonitrile was cooled at 10 and a solution of 200 g. of carbontetrabromide dissolved in 1000 ml. acetonitrile was added dropwise overa 30 min. period. After standing at 25 for 18 hrs. the reaction wasevaporated to dryness under vacuum. The residue was dissolved in 2 l.methanol and the pH adjusted to 11 by the addition of 4 N KOH. Afterstanding for 30 min. the pH was adjusted to 1 by the addition of 4 NHCl. Water, 1 1., was added and the methanol distilled under vacuum. Theresidue was filtered and the solid discarded. The filtrate was extractedwell with CH'Cl and the extracts discarded. The aqueous phase was madebasic with 4 N KOH and extracted with CI-ICl The CHCl extracts Werecombined and evaporated under vacuum to give 38 g. of crude product.This material was purified via chromatography over silica gel using aEtOAc:acetone:H O (8:5 :1) solvent system for elution. The productfractions were combined, evaporated and the residue recrystallized fromEtOAc to give 15 g. of methyl 7-bromo-6,7,8-tride0Xy-6-(5,6,7,7a xtetrahydro- 1-oxo-6u-propyl 1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)-l-thio-L-threo-u-D-galacto-octopyranoside having the followingcharacteristics: M.P. 147-148. [(11 +236 (0., 0.93, CHCl Analysis.Calcd.for C H BrN O S (percent): C, 46.25; H, 6.69; Br, 17.10; N, 5.99; S,6.86. Found (percent): C, 46.15; H, 6.62; Br, 17.34; N, 6.91; S, 6.69.

EXAMPLE 5 Methyl 6,8-dideoxy 6 (5,6,7,7aa-tetrahydro-1-oxo-6apropyl 1Hpyrrolo[1,2-c]imidazol 2-(3H)-yl)-1-thio-D-erythro-a-D-galacto-octopyranoside 1'-demethyllincomycinhydrochloride (2.0 g.) was dissolved in 200 ml. of water. The solutionwas then mixed with 20 ml. of an aqueous solution of formaldehyde (30%w./v.) and 20 ml. of 1 N aqueous sodium hydroxide. The mixture wasallowed to stand at room temperature for 3.5 hrs. Thin layerchromatography [silica gel G, methyl ethyl ketone, acetone, water(186:52:20 v./v.)] showed complete conversion of l'-demethyllincomycinto a new bioactive (S. lurea) compound. The mixture was thenfreeze-dried. The freeze-dried material was dissolved in 200 ml. ofwater and passed through a column containing ml. of Amberlite XAD-2resin (a non-ionic, macro-porous copolymer of styrene crosslinked withdivinyl benzene). The bioactive component was adsorbed on the resin andthen it was eluted with absolute methanol. The methanolic eluate wasconcentrated to dryness. The residue was dissolved in minimum amount ofmethanol and this solution was mixed with ether. The precipitatedmaterial was isolated by filtration and dried yielding 1.35 g. of methyl6,8-dideoxy-6(5,6,7, 7a-tetrahydro-1-oxo-6-propyl 1Hpyrrolo[1,2-c]imidazol-2(3H)-yl) 1 thio-Derythro-a-D-galacto-octopyranoside having the following properties: [111+169.9 (0., 1.0, water).

Analysisr-Calcd. for C H N O S (percent): C, 53.46; H, 7.92; N, 6.93; S,7.92; O, 23.76. Found (percent): C, 53.91; H, 8.37; N, 8.03; S, 7.48 O,23.79.

EXAMPLE 6 Methyl 6,8-dideoXy-6-(5,6,7,7aa-tetrahydro 1 oxo-3- methyl 6ozpropyl-lH-pyrrolo[1,2-c]imidazol-2(3H)-yl)-l-thio-D-erythro-a-D-galacto-octopyranoside sons OH1'-demethyllincom'ycin hydrochloride (2.0 g.) was dissolved in 200 ml.of water. The solution was mixed with 20 m1. of l N aqueous sodiumhydroxide and 20 ml. of acetaldehyde. The mixture was allowed to standat room temperature for 3.5 hrs. and then freeze-dried to give crudemethyl 6,8-dideoxy 6-(5,6,7-7aa-tetrahydro-l-oxo- 3 methyl6a-propyl-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)-1-thio-D-erythro-a-D-galacto octopyranoside which can be furtherpurified by the procedure of Example 5.

Following the procedures outlined in Examples 1 to 6, substituting theformaldehyde and acetaldehyde by propionaldehyde, butyraldehyde,pentanal, hexanal, heptanal, 2-hydroxyheptanal, octanal, nonanal,decanal, dodecanal, tetradecanal, hexadecan'al, octadecanal, andisomeric thereof; halogenated aldehydes such as chloroacetaldehyde and3-bromohexanal; alkoxy-substituted aldehydes such as2-meth0xybutyraldehyde; nitro-substituted aldehydes such asS-nitropentanal; dialkylaminosubstituted aldehydes such as3-dimethylaminoheptanal; and hydroxy-substituted aldehydes such asglyceraldehyde and glyoxal there are obtained the correspondingcompounds of Formula I wherein R is methyl, R is propyl, X is halogen orhydroxy as the case may be, and R is ethyl, propyl, butyl, pentyl,hexyl, l-hydroxyhexyl, heptyl, octayl, nonyl, undecyl, tridecyl,pentadecyl, nonadecyl, and the isomeric forms thereof; chloromethyl,2-bromopentyl, l-methoxypropyl, 4-nitrobutyl, 2 dimethylaminohexyl,1,2-dihydroxyethyl, and hydroxymethyl.

25 EXAMPLE 7 OH; I 110-- N 1'-demethyllincomycin hydrochloride (2.0 g.)was dissolved in 200 ml. of water and 100 ml. of absolute methanol. Thesolution was then mixed with 20 ml. of 1 N aqueous sodium hydroxide and20 ml. of furfuraldehyde. The mixture was allowed to stand at roomtemperature for 3.5 hrs. The mixture was then freeze-dried.

The freeze-dried material was dissolved in 200 ml. of water and thesolution was passed over 100 ml. of Amberlite XAD-Z. The bioactivecomponents were adsorbed on the resin and were eluted by absolutemethanol. Fractions containing the new bioactive component were combinedand the solution was concentrated to dryness. The residue (1.7 g.) wasfurther purified by chromatography over silica gel as described below.

The column was prepared from 300 g. of silica gel slurried in thesolvent consisting of chloroform-methanol (6:1 v./v.). The slurry wasadded in a glass column and allowed to settle under atmosphericpressure. The residue (1.7 g.) obtained as described above was dissolvedin 20 ml. of chloroform-methanol (6:1 v./v.) and the solution was mixedwith 20 g. of silica gel. The mixture was concentrated to dryness. Theobtained powder was added on the top of the column and the column wasthen eluted with the above solvent system. Fractions containing the newbioactive compound were concentrated to dryness. The residue wasdissolved in 10 ml. of chloroform and the solution was mixed with 70 ml.of ether. The precipitated material was separated by filtration (70mg.). The filtrate was mixed with 500 ml. of Skellysolve B. The newprecipitate formed was isolated by filtration yielding 400 mg. of methyl6,8-dideoxy-6-(5,6,7,7aa-tetrahydro 1-oxo- 6a propyl 3(2-furyl)-1H-pyrrolo[l,2-c]imidazol-2 (3H) yl)1thio-D-erythro-u-D-galacto-octopyranoside having the followingcharacteristics: [(11 +173 (c., 1.0, water).

Analysis.-Calcd. for C H N O S (percent): C, 56.22; H, 7.29; N, 5.96; O,23.83; S, 6.82. Found (percent): C, 52.79; H, 7.49; N, 5.68; S, 6.76.

Following the procedure of Example 7, substituting the furfuraldehyde,by nitrofurfuraldehyde, 5 hydroxyfurfuraldehyde, 4methoxyfurfuraldehyde, 3 mercaptofurfuraldehyde, 5acetoxyfurfuraldehyde, 3 (methylthio) furfuraldehyde, 3,5dichlorofurfuraldehyde, or 5 dimethylaminofurfuraldehyde, there areobtained the compounds of Example 7 in which the furyl group issubstituted by S-nitro, S-hydroxy, 4-methoxy 3 mercapto, S-acetoxy, 3(methylthio), 3,5 dichloro, or S-dimethylamino groups.

Also in place of furfuraldehyde there can be substituted any of thealdehydes where R contains or is a hetero cyclic radical, furyl,thienyl, pyridyl, or indolyl.

26 EXAMPLE 8 Methyl 6,8 dideoxy 6 (5,6,7,7aa tetrahydro loxo 3 phenyl6oz propyl 1H pyrrolo[l,2-c] imidazol (2(3H) yl) 1 thio D erythro a D-galacto-octopyranoside ,6-(5,6,7,7au tetrahydro 1 oxo 3 phenyl 6ozpropyl1H pyrrolo[l,2-c]imidazol 2(3H)-yl)-1-thio- D-erythro a D galactooctopyranoside which can be further purified by the procedure of Example5.

EXAMPLE 9 Methyl 7-bromo 6,7,8 trideoxy 6 (5,6,7,7aa-tetrahydro 1 oxo 6apropyl-S-p-bromophenyl 1H- pyrrolo[l,2-c]imidazol 2(3H) yl) 1 thio-L-threo-a-D-galacto-octopyranoside 1'-demethyl 7 deoxy 7 (S)bromolincomycin (5 g.) was refluxed with 10 g. of p-bromobenzaldehyde in200 ml. of tetrahydrofuran containing 5 g. of wateradsorbent polymercommonly known as a molecular sieve (Linde molecular sieve, 4A, LindeCompany) for 12 hrs. The molecular sieve was removed and the solutionconcentrated. The residue was chromatographed over 1.2 kg. of silica gelusing acetone for elution. Fractions of 20 ml. each were collected.Fractions 172-235 were pooled and evaporated. The residue was dissolvedin 20 ml. of ether and precipitated by addition of 300 ml. ofSkellysolve B (technical hexane). The precipitate was collected anddried giving 700 mg. of methyl 7-bromo- 6,7,8 trideoxy 6 (5,6,7,7aatetrahydro 1 oxo- Got-propyl 3 p bromophenyl 1H pyrrolo[1,2-c] imidazol2(3H) yl) 1 thio-L-threo-a-D-galactooctopyranoside having the followingcharacteristics: [0:11) 197 (c., 1.0, EtOH).

Analysis.-Calcd. for C H Br N O S (percent): C, 46.30; H, 5.47; Br,25.72; N, 4.50; S, 5.14. Found (percent): C, 47.74; H, 5.62; Br, 25.45N, 4.05; S, 4.96.

27 EXAMPLE 1o- Methyl 7-chloro 6,7,8 trideoxy 6 (5,6,7,7au-tetrahydro 1oxo 60: propyl 3 p chlorophenol-IH- pyrrolo[1,2-c]imidazol 2(3H) yl) 1thio-L- threo-ot-D-galacto-octopyranoside (l SCHa Following theprocedure of Example 9, 3 g. of 1'- demethylclindamycin was treated with4.2 g. of p-chlorobenzaldehyde in 150 ml. of tetrahydrofuran containing3 g. of molecular sieve. Chromatography of the crude product over 1 kg.of silica gel using acetone-Skellysolve B (1:1) for elution. Twenty ml.fractions were collected. Fractions 120-160 ml. were pooled andevaporated to yield 350 mg. of methyl 7-chloro 6,7,8 trideoxy-6-(5,6,7,7aa-tetrahydro 1 oxo 6a propyl 3 pchlorophenyl 1Hpyrrolo[1,2-c]imidazol 2(3H)-yl)- 1-thio-L-threo a D galactooctopyranoside having the following characteristics: +182 (c., 1.0,EtOH).

Analysis.-Calcd. for C H Cl N O S (percent): C, 54.13; H, 6.39; CI,13.16; N, 5.26; S, 6.01. Found (percent): C, 54.80; H, 6.56; CI, 13.64;N, 5.31; S, 5.77.

EXAMPLE 11 Methyl 7-chloro 6,7,8 trideoxy 6 (5,6,7,7aa-tetrahydro 1 oxo70c propyl 3 p nitrophenyl 1H- pyrrolo[1,2-c]imidazol 2(3H) yl) 1 thioL- threo-oc-D-galacto-octopyranoside l I SCH: 011

Following the procedure of Example 9, 3 g. of 1'- demethylclindamycinwas treated with 4.5 g. of p-nitrobenzaldehyde. After chromatography(fractions 120-160 ml.) there was obtained 1.05 g. of methyl7-chloro-6,7,8- trideoxy 6 (5,6,7,7aa tetrahydro 1 oxo 6apropyl 3 pnitrophenyl 1H pyrrolo[1,2-c]imidazol- 2(3H) yl) 1thio-L-threo-u-D-galacto-octopyranoside having the followingcharacteristics: [0th, +169 (c., 1.0, EtOH).

Analysis.-Calcd. for C H ClN 'O S (percent): C, 53.04; H, 6.26; Cl,6.44; N, 7.73; S, 5.89. Found (percent): C, 53.75; H, 6.43; Cl, 6.47; N,8.10; S, 5.65.

Following the procedure of Examples 8 to 11, but substituting othersubstituted aromatic aldehydes such as salicylaldehyde, piperonal, andvanillin, there are obtained the corresponding compounds of Formula Iwherein R is methyl, R is propyl, and X is halogen or hydroxy as thecase may be, and R is 2-hydroxyphenyl, 3,4-methylenedioxyphenyl, or4-hydroxy-3-methoxyphenyl.

28 EXAMPLE 12 H VO CH3 Ll -OCHa I OH scrn Part A-lZ MethylN-acetyl-6,7-aziridino-6-deamino-7-deoxy-2,3,4-tri-O-acetyl-a-thiolincosaminide Ac-N To a solution of 2.0 gms. ofmethyl 6,7-aziridino 6- deamino 7 deoxy-a-thiolincosaminide in 20 ccs.of pyridine was added with stirring 10 ccs. of acetic anhydride and thereaction mixture left overnight at room temperature. The volatilematerial was removed as completely as possible from the reaction mixtureon a rotary evaporator at 40 C./7 mm., finally at high vacuum, to acolorless solid. The resulting solid was dissolved in chloroform,stirred with aqueous cadmium chloride to remove the pyridine, filteredand the chloroform layer washed twice with water, and dried overanhydrous sodium sulfate. On removal of the solvent on the rotaryevaporator at 40 C./7 mm. methyl N-acetyl 6,7 aziridino 6- deamino 7deoxy 2,3,4 tri-O-acetyl 0c thiolincosaminide was obtained as acolorless crystalline solid, weight 3.1 gms. Recrystallization fromethyl acetate- Skellysolve B (technical hexane) gave colorless prismaticneedles having the following characteristics: M.P. 173.5- 175 C. [02]+222 (c., 0.912, CHCl Analysis.-Calcd. for C H O NS (percent): C, 50.61;H, 6.25; N, 3.47; S, 7.95. Found (percent): C, 50.43; H, 6.33; N, 3.41S, 8.31.

M01. wt. calcd.: 403.45.

Found (mass spec.): 403.

Part B-12 Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S)methoxyu-thiolincosaminide A mixture of 5 gms. of methyl-N-acetyl 2,3,4O triacetyl 6,7 aziridino 6 deamino 7 deoxy octhiolincosaminide, 50 ccs.methanol, and 5 ccs. glacial acetic acid was heated under gentle refluxin an oil bath at C. for six hours. The solvent was removed from thecolorless solution at 40 C./ 7 mm. on a rotary evaporator yielding apale yellow syrup which crystallized. The crystals were taken up inmethylene chloride solution, washed with saturated aqueous sodiumbicarbonate, then with water, and then dried over anhydrous sodiumsulfate. Removal of the solvent as above gave methyl N-acetyl 2,3,4 triO acetyl 7(S) methoxy 7- deoxy a thiolincosaminide as colorless crystals(5.31 gms.). Crystallization from ethyl acetate-Skellysolve B 29 gavefine colorless needles having the following properties: M.P. 235-236 C.[e1 +205 (c., 0.9952, CHCl Analysis.-Calcd. for C H O NS (percent): C,49.64; H, 6.71; N, 3.22; S, 7.36; OMe, 7.13. Found (percent): C, 49.77;H, 6.92; N, 3.65; S, 7.90; OMe, 7.38.

M01. wt. calcd.: 435.49.

Found (mass spec.): 435.

On hydrazinolysis by the procedure of Part C-12 there is obtained methyl7-deoxy-7(S)-methoxy-a-thiolincosaminide.

Part C-12 Methyl 7 deoxy 70S) methoxy ct thiolincosaminide (methyl 6,8dideoxy 7 O methyl 6 amino-1 thio L threo c D galacto octopyranoside) Asolution of 3.2 gms. of methyl N-acetyl-2,3,4-tri-O- acetyl 7deoxy-7'(S)-methoxy-a-thiolincosaminide in 25 gms. of hydrazine hydratewas heated under gentle reflux with stirring in an oil-bath at 145 C.overnight. The solvent was removed from the colorless solution ascompletely as possible by distillation from an oil-bath at 100 C./15 mm.and finally at high vacuum to give methyl 7-deoxy-7(S)-methoxy-a-thiolincosaminide as a colorless syrup. The syrupwas chromatographed on 750 gms. of silica gel in a 4.8 97 cm. columnusing 1 MeOHzlO CHCl as the solvent system. After 1.4 liter forerun, 50ml. fractions were collected. Fractions 281-600 were pooled andevaporated to dryness yielding 2.06 gms. methyl7-deoxy-7(S)-methoxy-a-thiolincosaminide which on crystallization fromacetonitrile yielded colorless needles having the followingcharacteristics: M.P. 154- 155 C. [0th, +260 (c., 0.5635, H O).

Analysis.Calcd. for C H O NS (percent): C, 44.92; H, 7.92; N, 5.24; S,12.00; OMe, 11.61. Found (percent): C, 45.20; H, 7.96; N, 5.08; S,12.19; OMe, 11.86.

Mol. wt. calcd.: 267.35.

Found (mass spec.): 267.

Part D-12 1'-carbobenzoxy-7-deoxy-7 ('S)-methoxylincomycin Dhydrochloride Cis and trans-l-carbobenzoxy-4-propyl-L-proline (2.33 g.)was dissolved in 150 ml. of acetonitrile containing 1.12 ml. oftriethylamine. The solution was cooled to 0 and 1.18 ml. ofisobutylchloroformate added. After min. at 0, a solution of 2.17 g. ofmethyl 7(S)-methoxya-thiolincosaminide in 40 ml. of water was added. Themixture was stirred for 2 hrs. at ambient temperature and the solventdistilled in vacuo to yield a crystalline residue.

The crystals were collected by filtration, washed and dried to yieldmethyl N-(1-carbobenzoxy-4-trans andcispropyl-L-prolyl)-7(S)-methoxylincosaminide.

30 Part E-l 2 7-deoxy-7(S)-methoxylincomycin D hydrochloride and 7-deoxy 7(S) methoxyallolincomycin D hydrochloride (cis and trans forms) tK l? A portion of the crude product from above was dissolved in 50 ml.of methanol and 0.5 g. of 10% palladium on charcoal added. The mixturewas shaken under 35 lbs. of hydrogen pressure for 4 hrs. TLC showedpartial hydrogenolysis. An additional 0.5 g. of catalyst was added andhydrogenation continued for 18 hrs. The catalyst was removed byfiltration. The residue was chromatographed over silica gel, and themore polar fraction collected. It weighed mg. It was converted to thehydrochloride in the usual manner.

Part F-12 Methyl 6,8 dideoxy 7 methoxy 6 -(5,6,7,7aa-tetrahydro-l-oxo-6aand B propyl-lH-pyrroldl,2-c]-imidazol -2 (3H) -yl)1-thio-L-threo-u-D-galactooctopyranoside Following the procedure ofExample 1 substituting the 1'-dimethylclindamycin hydrochloride by themixed 7(8)- methoxylincomycin D hydrochloride and7('S)-methoxyallolincomycin D hydrochloride of Part E12, there isobtained methyl 6,8-dideoxy-7-methoxy-6-(5,6,7,7aa-tetra-2(3'H)-yl)-1-thio-L-threo-u-D-galacto-octopyranoside.

By substituting the methanol in Part B-12 by ethanol or otherloweralkanol the corresponding methyl 6,8-dideoxy-7-loweralkoxy 6(5,6,7,7aa-tetrahydro 1 OXO-6aand fl-propyl 1Hpyrrolo[1,2-c]irnidazol-2(3H)-yl)-lthio-L-threo-a-D-galacto-octopyranosidesare obtained.

Following the procedure of Example 12 substituting in Part B-12 themethanol by methyl sulfide, Z-hydroxyethyl methyl sulfide, phenylsulfide, ethyl sulfide, and isopropyl methyl sulfide, there are obtainedmethyl 6,7,8- trideoxy-7(S) (methylthio)-, 7(S) (ethylthio)-, 7(5)-(propylthio)-, 7(S)- (phenylthio)-, and 7(S)-(2hydroxyethylthio) 65,6,7,7aa tetrahydro 1 oxo 6aand p pro-pyl 1H pyrrolo[l,2-c]imidazol2(3H) yl)-1- thio-L-threo-a-D-galactooctopyranosides.

EXAMPLE 13 A mixture of 2.4 g. 7(S)-chloro-7-deoxy-4-depropyllincomycin, 50 ml. water, 5 ml. formaldehyde, and 1 N NaOH to pH 10 wasstirred for 2 hrs. The reaction mixture was extracted with chloroformand the chloroform extract evaporated to dryness yielding 0.8 g. ofsolid 3 1 which on recrystallization from ethyl acetate gave 500 mg. ofmethyl 7-chloro-6,7,8-trideoxy-6-(5,6,7,7aa-tetra- TZOZI I |l SR ELZwherein R, R R and X are as given below which comprises reacting undernon-acid conditions a compound of the formula with an aldehyde of theformula R CHO wherein X is chlorine, bromine, iodine, hydroxy,loweralkoxy, hydroxyloweralkoxy, sulfhydryl, lower-alkylthio,hydroxyloweralkylthio, or an aromatic hydrocarbon-thio radicalsubstituted by zero through 3 hydroxy, halo, nitro, dialkylamino groupscontaining in all not more than 12 carbon atoms; R is alkyl of one to 4carbon atoms, inclusive; or a radical of the formula --CH CH OR whereinR is hydrogen or alkyl of one to 4 carbon atoms. inclusive; R ishydrogen or lower-alkyl; R is hdyrogen or an aliphatic, cycloaliphatichydrocarbon radical having from zero through three valences satisfied byhalogen, alkoxy, alkenyloxy, alkylthio, alkenylthio, hydroxy, nitro,epoxy, epoxyalkoxy, alkanoyloxy, dialkylamino, carboxy, or lowercarbalkoxy containing in all not more than 18 carbon atoms; or anaromatic hydrocarbon radical of the benzene series having from zerothrough three valences satisfied by hydroxy, alkoxy, alkanoyloxy,benzoyloxy, phenoxy, tolyloxy, halogen, nitro, amino, mercapto,alkylthio, amino, alkylamino, dialkylamino, or methylenedioxy containingin all not more than 18 carbon atoms; a hydrocarbon radical containing aheterocycle of the group furan, thiophene, pyridine, and indole havingzero to three substituents of the group hydroxy, alkoxy, alkanoyloxy,benzyloxy, phenoxy, alkoxyphenyl, alkoxybenzyl, mercapto, alkylthio,phenylthio, benzylthio, halogen, nitro, amino, alkylamino, dialkylamino,carboxy, and carbalkoxy and containing in all not more than 18 carbonatoms.

2. A process of claim 1 wherein R is an aliphatic or cycloaliphatichydrocarbon radical having from zero through three valences satisfied byhalogen, alkoxy, alkenyloxy, alkylthio, alkenylthio, hydroxy, mercapto,nitro, epoxy, epoxyalkoxy, alkanoyloxy, dialkylamino, carboxy, orcarbalkoxy containing in all not more than 18 carbon atoms.

3. A process of claim 2 wherein R is hydrogen.

4. A process of claim 2 wherein R is lower alkyl.

5. A process of claim 3 wherein X is chlorine or bromine.

6. A process of claim 4 wherein X is chlorine or bromine.

7. A process of claim 1 in which R is a hydrocarbon radical containing aheterocycle of the group furan, thiophene, pyridine, and indole havingzero to three substituents of the group hydroxy, alkoxy, alkanoyloxy,benzyloxy, phenoxy, alkoxyphenyl, alkoxybeuzyl, mercapto, alkylthio,phenylthio, benzylthio, halogen, nitro, amino, alkylamino, dialkylamino,carboxy, and carbalkoxy and containing in all not more than 18 carbonatoms.

8. A process of claim 7 in which R is furyl.

9. A compound of the formula ..N R2 H O OH I wherein X is chlorine,bromine, iodine, hydroxy, loweralkoxy, hydroxyloweralkoxy, sulfhydryl,lower-alkylthio, hydroxyloweralkylthio, or an aromatic hydrocarbon-thioradical substituted by zero through 3 hydroxy, halo, nitro, dialkylaminogroups containing in all not more than 12 carbon atoms; R is alkyl ofone to 4 carbon atoms, inclusive; or a radical of the formula CH CH ORwherein R is hydrogen or alkyl of one to 4 carbon atoms, inclusive; R ishydrogen or lower-alkyl; R is hydrogen or an aliphatic, cycloaliphatichydrocarbon radical having from zero through three valences satisfied byhalogen, alkoxy, alkenyloxy, alkylthio, alkenylthio, hydroxy, mercapto,nitro, epoxy, epoxyalkoxy, alkanoyloxy, dialkylamino, carboxy, or lowercarbalkoxy containing in all not more than 18 carbon atoms; or anaromatic hydrocarbon radical of the benzene series having from zerothrough three valences satisfied by hydroxy, alkoxy, alkanoyloxy,benzyloxy, phenoxy, tolyloxy, halogen, nitro, amino, mercapto,alkylthio, alkylamino, dialkylamino, or methylenedioxy containing in allnot more than 18 carbon atoms; a hydrocarbon radical containing aheterocycle of the group furan, thiophene, pyridine, and indole havingzero to three substituents of the group hydroxy, alkoxy, alkanoyloxy,benzyloxy, phenoxy, alkoxyphenyl, alkoxybenzyl, mercapto, alkylthio,phenylthio, benzylthio, halogen, nitro, amino, alkylamino, dialkylamino,carboxy, and carbalkoxy and containing in all not more than 18 carbonatoms.

10. A compound of claim 9 wherein R is an aliphatic or cycloaliphatichydrocarbon radical having from zero through three valences satisfied byhalogen, alkoxy, alkenyloxy, alkylthio, alkenylthio, hydroxy, mercapto,nitro, epoxy, epoxyalkoxy, alkanoyloxy, dialkylamino, carboxy, orcarbalkoxy containing in all not more than 18 carbon atoms. a

11. A compound of claim 9 wherein R is hydrogen.

12. A compound of claim 10 wherein R is lower alkyl.

13. A compound of claim 10 wherein X is chlorine or bromine.

14. A compound of claim 11 wherein X is chlorine or bromine.

15. A compound of claim 12 wherein X is chlorine or bromine.

1-6. A compound of claim 9 in which R is a hydrocarbon radicalcontaining a heterocycle of the group furan, thiophene, pyridine, andindole having zero to three substituents of the group hydroxy, alkoxy,alkanoyloxy, benzyloxy, phenoxy, alkoxyphenyl, alkoxybenzyl, mercapto,alkylthio, phenylthio, benzylthio, halogen, nitro, amino, alkylamino,dialkylamino, carboxy, and carbalkoxy and containing in all not morethan 18 carbon atoms.

17. A compound of claim 16 in which R is fury].

